The present invention relates to new substituted dimeric compounds having very valuable pharmacological properties in respect of melatoninergic receptors.
From the prior art dimeric naphthalenic structures are known (J. Chem. Soc., Dalton Trans., 1979, (10), pp. 1497-502) that have been studied for their coordination properties in metal complexes. Indole dimers have also been described for their xe2x80x9ccurare-likexe2x80x9d activity (Khim.-Farm. Zh., 1984, 18 (1), pp. 29-31).
Owing to their novel structure, the compounds of the present invention are new and have pharmacological properties that are very valuable in respect of melatoninergic receptors.
Numerous studies in the last ten years have demonstrated the key role of melatonin (N-acetyl-5-methoxytryptamine) in many physiopathological phenomena and in the control of the circadian rhythm. Its half-like is quite short, however, owing to the fact that it is rapidly metabolised. Great interest therefore lies in the possiblity of providing the clinician with melatonin analogues that are metabolically more stable, have an agonist or antagonist character and that may be expected to have a therapeutic effect that is superior to that of the hormone itself.
In addition to their beneficial action on circadian rhythm disorders (J. Neurosurg. 1985, 63, pp. 321-341) and sleep disorders (Psychopharmacology, 1990, 100, pp. 222-226), ligands of the melatoninergic system have valuable pharmacological properties in respect of the central nervous system, especially anxiolytic and antipsychotic properties (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp. 264-272) and analgesic properties (Pharmacopsychiat., 1987, 20, pp. 222-223) as well as for the treatment of Parkinson""s disease (J. Neurosurg. 1985, 63, pp. 321-341) and Alzheimer""s disease (Brain Research, 1990, 528, pp. 170-174). Those compounds have also demonstrated activity in relation to certain cancers (Melatoninxe2x80x94Clinical Perspectives, Oxford University Press, 1988, pp. 164-165), ovulation (Science 1987, 227, pp. 714-720), diabetes (Clinical Endocrinology, 1986, 24, pp. 359-364), and in the treatment of obesity (International Journal of Eating Disorders, 1996, 20 (4), pp. 443-446).
Those various effects are exerted via the intermediary of specific melatonin receptors. Molecular biology studies have demonstrated the existence of a number of receptor sub-types that are capable of binding that hormone (Trends Pharmacol. Sci., 1995, 16, p 50; WO 97.04094). It has been possible, for various species, including mammals, for some of those receptors to be located and characterised. In order to be able to understand the physiological functions of those receptors better, it is of great advantage that specific ligands are available. Moreover, such compounds, by interacting selectively with one or other of those receptors, may be excellent medicaments for the clinician in the treatment of pathologies associated with the melatoninergic system, some of which have been mentioned above.
In addition to the fact that the compounds of the present invention are new, they show very strong affinity for melatonin receptors and/or selectivity for one or other of the melatoninergic receptor sub-types.
The present invention relates more especially to compounds of formula (I):
A-G1-Cy-G2-Cy-G3-Bxe2x80x83xe2x80x83(I) 
wherein:
A represents a grouping of formula 
wherein:
Q represents a sulphur or oxygen atom,
R1, R2 and R3, which may be identical or different, represent a hydrogen atom or a group Ra (wherein Ra represents an unsubstituted or substituted linear or branched (C1-C6)alkyl group, an unsubstituted or substituted linear or branched (C2-C6)alkenyl group, an unsubstituted or substituted linear or branched (C2-C6)alkynyl group, an unsubstituted or substituted (C3-C8)-cycloalkyl group, an unsubstituted or substituted cycloalkyl-(C3-C8)alkyl (C1-C6)group in which the alkyl moiety is linear or branched, a polyhalo-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an aryl group, an aryl(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an aryl(C2-C6)alkenyl group in which the alkenyl moiety is linear or branched, a heteroaryl group, a heteroaryl(C1-C6)alkyl group in which the alkyl moiety is linear or branched or a heteroaryl(C2-C6)alkenyl group in which the alkenyl moiety is linear or branched),
or the groupings R2 and R3 form, with the nitrogen atom carrying them, a group selected from piperazinyl, piperidinyl and pyrrolidinyl, 
G1 and G3, which may be identical or different, represent a linear or branched alkylene chain having from 1 to 4 carbon atoms that is optionally substituted by one or more identical or different groups selected from hydroxy, carboxy, formyl, Ra, ORa, COORa and CORa (wherein Ra is as defined hereinbefore),
Cy represents
a ring structure of formula (II): 
wherein:
X and Y, which may be identical or different, represent a sulphur, oxygen or carbon atom, or a CH or CH2 group,
R4 represents a hydrogen or halogen atom, or a CF3, hydroxy, carboxy, formyl, amino, NHRa, NRaR1a, NHCORa, CONHRa, Ra, ORa, CORa or COORa group (wherein Ra is as defined hereinbefore and R1a can have any of the meanings of Ra),
the symbol  means that the bonds are single or double, with the proviso that the valency of the atoms is respected,
wherein G2 substitutes the benzene ring, and G1 (and G3 respectively) substitutes the ring containing X and Y,
or a ring structure of formula (III): 
wherein:
Z represents a sulphur or oxygen atom, or a CH, CH2, NH, NSO2Ph or NRa group (wherein Ra is as defined hereinbefore),
D represents a benzene or pyridine ring,
R4 is as defined hereinbefore,
the symbol  means that the bond is single or double, with the proviso that the valency of the atoms is respected,
wherein G2 substitutes the D ring, and G1 (and G3 respectively) substitutes the ring containing Z,
it being understood that the two rings (Cy) of the compounds of formula (I) represent the same basic ring structure (indole/indole, naphthalene/naphthalene, benzofuran/benzofuran, etc.), but the substituent R4 may be different,
G2 represents a chain of formula (IV): 
wherein:
W1, W2 and W3, which may be identical or different, represent a bond, an oxygen or sulphur atom, or a CH2, CHRa, NH or NRa group (wherein Ra is as defined hereinbefore),
n represents an integer wherein 0xe2x89xa6nxe2x89xa66,
m represents an integer wherein 0xe2x89xa6mxe2x89xa66,
with the proviso that it is not possible to have two consecutive hetero atoms and that the chain of formula (IV) so defined may have one or more unsaturated bonds,
wherein:
the compound of formula (I) cannot represent diethyl 2-(acetylamino)-2-{[5-({3-[2-(acetylamino)-3-ethoxy-2-(ethoxycarbonyl)-3-oxopropyl]-1H-indol-5-yl} methyl)-1H-indol-3-yl]methyl}malonate,
or N-{2-[5-({3-[2-(acetylamino)ethyl]-1H-indol-5-yl}methyl)-1H-indol-3-yl]-ethyl}acetamide,
xe2x80x9carylxe2x80x9d is understood to mean the groups naphthyl, phenyl and biphenyl,
xe2x80x9cheteroarylxe2x80x9d is understood to mean any saturated or unsaturated mono- or bi-cyclic group containing from 5 to 10 atoms and containing from 1 to 3 hetero atoms selected from nitrogen, sulphur and oxygen,
it being possible for the xe2x80x9carylxe2x80x9d and xe2x80x9cheteroarylxe2x80x9d groups to be substituted by one or more identical or different radicals selected from hydroxy, carboxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl, polyhalo-(C1-C6)-alkyl in which the alkyl moiety is linear or branched, formyl, cyano, nitro, amino, linear or branched (C1-C6)alkylamino, di-(C1-C6)alkylamino in which each alkyl moiety is linear or branched, and halogen atoms,
the term xe2x80x9csubstitutedxe2x80x9d applied to the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d means that those groups are substituted by one or more identical or different radicals selected from hydroxy, linear or branched (C1-C6)alkoxy, polyhalo-(C1-C6)alkyl in which the alkyl moiety is linear or branched, amino, linear or branched (C1-C6)alkylamino, di-(C1-C6)alkylamino in which each alkyl moiety is linear or branched, and halogen atoms,
the term xe2x80x9csubstitutedxe2x80x9d applied to the terms xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9ccycloalkylalkylxe2x80x9d means that the cyclic moiety of those groups is substituted by one or more identical or different radicals selected from hydroxy, linear or branched (C1-C6)alkoxy, polyhalo-(C1-C6)alkyl in which the alkyl moiety is linear or branched, amino, linear or branched (C1-C6)alkylamino, di-(C1-C6)alkylamino in which each alkyl moiety is linear or branched, and halogen atoms,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred compounds of the invention are the compounds of formula (I) in which Cy represents a ring structure of formula (II), such as, for example, naphthalene or tetrahydronaphthalene, or of formula (III), such as, for example, indole, azaindole, benzothiophene or benzofuran.
Advantageously, the invention relates to the compounds of formula (I) wherein G2 represents a single bond, or a grouping xe2x80x94W4xe2x80x94(CH2)pxe2x80x94Wxe2x80x24xe2x80x94 (wherein W4 and Wxe2x80x24, which may be identical or different, represent an oxygen or sulphur atom, or an NH or NRa group, and p represents an integer wherein 1xe2x89xa6pxe2x89xa612), such as, for example, the grouping xe2x80x94Oxe2x80x94(CH2)pxe2x80x94Oxe2x80x94 (wherein p is as defined hereinbefore),
or a grouping of formula xe2x80x94W4xe2x80x94(CH2)pxe2x80x2xe2x80x94Wxe2x80x24xe2x80x94(CH2)pxe2x80x3xe2x80x94Wxe2x80x34xe2x80x94 (wherein W4, Wxe2x80x24 and Wxe2x80x34, which may be identical or different, represent an oxygen or sulphur atom, or an NH or NRa group, and pxe2x80x2 and pxe2x80x3 are two integers wherein 2xe2x89xa6pxe2x80x2+pxe2x80x3xe2x89xa612), such as, for example, the grouping xe2x80x94Oxe2x80x94(CH2)pxe2x80x2xe2x80x94Oxe2x80x94(CH2)pxe2x80x3xe2x80x94Oxe2x80x94 (wherein pxe2x80x2 and pxe2x80x3 are as defined hereinbefore).
Preferred substituents A and B of the invention are the groupings NR1C(Q)R2, NR1C(Q)NR2R3 and C(Q)NR2R3, and more especially the groupings NR1COR2 and CONR2R3.
More especially still, the invention relates to the compounds of formula (I) which are:
N-(2-{7-[2-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)ethoxy]-1-naphthyl}ethyl)-acetamide,
N-(2-{7-[3-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)propoxy]-1-naphthyl}-ethyl)acetamide,
N-(2-{7-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-1-naphthyl }ethyl)-acetamide,
N-[2-(7-{[6-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)hexyl]oxy}-1-naphthyl)-ethyl]acetamide,
N-[2-(7-{[8-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)octyl]oxy}-1-naphthyl)-ethyl]acetamide,
N-[2-(7-{[10-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)decyl]oxy}-1-naphthyl)-ethyl]acetamide,
N-[2-(7-{[5-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)pentyl]oxy}-1-naphthyl)-ethyl]acetamide,
N-(2-{7-[4-({8-[2-(2-furoylamino)ethyl]-2-naphthyl}oxy)butoxy]-1-naphthyl}-ethyl)-2-furamide,
2-bromo-N-[2-(7-{4-[(8-{2-[(bromoacetyl)amino]ethyl}-2-naphthyl)oxy]-butoxy}-1-naphthyl)ethyl]acetamide,
N-[2-(7-{4-[(8-{2-[(cyclopropylcarbonyl)amino]ethyl}-2-naphthyl)oxy]-butoxy}-1-naphthyl)ethyl]cyclopropanecarboxamide,
N-(2-{7-[4-({8-[2-(3-butenoylamino)ethyl]-2-naphthyl}oxy)butoxy]-1-naphthyl}-ethyl)-3-butenamide,
N-(2-{7-[4-({8-[2-(acetylamino)ethyl]-7-methoxy-2-naphthyl}oxy)butoxy]-2-methoxy-1-naphthyl}ethyl)acetamide,
N-[2-(7-{2-[2-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)ethoxy]ethoxy}-1-naphthyl)ethyl]acetamide,
tert-butyl 2-{7-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-1-naphthyl}ethyl carbamate,
N-{2-[7-(4-{[8-(2-aminoethyl)-2-naphthyl]oxy}butoxy)-1-naphthyl]ethyl}-acetamide hydrochloride
methyl {7-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-1-naphthyl} acetate,
{7-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-1-naphthyl}-acetic acid,
N-(2-{7-[4-({8-[2-(acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthalenyl}oxy)-butoxy]-1,2,3,4-tetrahydro-1-naphthalenyl}ethyl)acetamide,
N-{2-[5-(4-{[3-[2-(acetylamino)ethyl]-1-(phenylsulphonyl)-1H-indol-5-yl]-oxy}butoxy)-1-(phenylsulphonyl)-1H-indol-3-yl]ethyl}acetamide,
N-(2-{5-[4-({3-[2-(acetylamino)ethyl]-1H-indol-5-yl}oxy)butoxy]-1H-indol-3-yl}ethyl)acetamide,
N-(2-{5-[4-({3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl }oxy)butoxy]1-benzofuran-3-yl}ethyl)acetamide,
N-(2-{5-[4-({3-[2-(acetylamino)ethyl]-1-benzothien-5-yl}oxy)butoxy]-1-benzothien-3-yl}ethyl)acetamide,
N-(2-{5-[4-({3-[2-(acetylamino)ethyl]-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl}oxy)butoxy]-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}ethyl)acetamide,
N-(2-{5-[4-({3-[2-(acetylamino)ethyl]-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl}oxy)propoxy]-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}ethyl)acetamide,
N-[2-(7-{8-[2-(acetylamino)ethyl]-2-naphthyl}-1-naphthyl)ethyl]acetamide,
N-{2-[5-{3-[2-(acetylamino)ethyl]-1H-indol-3-yl}-1H-indol-3-yl]ethyl}acetamide.
The enantiomers, diastereoisomers and addition salts with a pharmaceutically acceptable acid or base of the preferred compounds of the invention form an integral part of the invention.
The present invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (V):
A-G1-Cy-OMexe2x80x83xe2x80x83(V) 
wherein A, G1 and Cy are as defined for formula (I),
which is subjected to demethylation using conventional agents, such as HBr, AlCl3, AlBr3, BBr3 or Lewis acid/nucleophile binary systems, such as, for example, AlCl3/PhCH2SH or BBr3/Me2S, to obtain a compound of formula (VI):
A-G1-Cy-OHxe2x80x83xe2x80x83(VI) 
wherein A, G1 and Cy are as defined hereinbefore,
which is converted, in conventional manner,
by the action of, for example, sodium N,N-dimethylthiocarbamate to the corresponding thiol of formula (VII):
A-G1-Cy-SHxe2x80x83xe2x80x83(VII) 
wherein A, G1 and Cy are as defined hereinbefore,
or to the corresponding amine compound of formula (VIII):
A-G1-Cy-NHRxe2x80x2axe2x80x83xe2x80x83(VIII) 
wherein A, G1 and Cy are as defined hereinbefore and Rxe2x80x2a can have any of the meanings of Ra as defined for formula (I) and can also represent a hydrogen atom,
which compounds of formulae (VI), (VII) and (VIII) represent the compound of formula (IX):
A-G1-Cy-W4Hxe2x80x83xe2x80x83(IX) 
wherein W4 represents an oxygen or sulphur atom, or an NH or NRa group (wherein Ra is as defined hereinbefore),
which compound of formula (IX) is condensed with:
a compound of formula (X): 
wherein Hal represents a bromine, chlorine or iodine atom, and n, W2 and m are as defined for formula (I), (with the proviso that it is not possible to have two consecutive hetero atoms and that the chain so defined may have one or more unsaturated bonds),
or a compound of formula (XI): 
wherein Hal, W2, n and m are as defined hereinbefore and Alk represents an alkyl radical (with the proviso that it is not possible to have two consecutive hetero atoms and that the chain so defined may have one or more unsaturated bonds), followed by reduction,
to yield a compound of formula (XII):
A-G1-Cy-W4xe2x80x94(CH2)nxe2x80x94W2xe2x80x94(CH2)mxe2x80x94OHxe2x80x83xe2x80x83(XII) 
wherein A, G1, Cy, W2, W4, n and m are as defined for formula (I) (with the proviso that it is not possible to have two consecutive hetero atoms in the W4xe2x80x94(CH2)nxe2x80x94W2xe2x80x94(CH2)mxe2x80x94OH chain and that the chain so defined may have one or more unsaturated bonds),
the hydroxyl function of which is converted in conventional manner to a leaving group, such as, for example, a mesylate, a tosylate, or a halogen compound, to yield a compound of formula (XIIxe2x80x2):
A-G1-Cy-W4xe2x80x94(CH2)nxe2x80x94W2xe2x80x94(CH2)m-Exe2x80x83xe2x80x83(XIIxe2x80x2) 
wherein A, G1, Cy, W4, n, W2 and m are as defined hereinbefore and E represents a mesyl or tosyl group or a halogen atom,
which is subjected to the action of a compound of formula (XIII):
B-G3-Cy-Wxe2x80x24Hxe2x80x83xe2x80x83(XIII) 
wherein B, G3 and Cy are as defined for formula (I) and Wxe2x80x24 can have the same meanings as W4 defined hereinbefore,
to yield a compound of formula (I/a), a particular case of the compounds of formula (I):
A-G1-Cyxe2x80x94W4xe2x80x94(CH2)nxe2x80x94W2xe2x80x94(CH2)mxe2x80x94Wxe2x80x24-Cy-G3-Bxe2x80x83xe2x80x83(I/a) 
wherein A, G1, Cy, W4, n, W2, m, Wxe2x80x24, G3 and B are as defined hereinbefore,
(which compounds of formula (I/a) wherein the groupings A-G1-Cy-W4- and Wxe2x80x24-Cy-G3-B are identical can be obtained directly from a compound of formula (IX) which is condensed, in a basic medium, with a compound of formula (Xxe2x80x2): 
wherein Hal, n, m and W2 are as defined hereinbefore),
or converted using, for example, phenyl bis(trifluoromethanesulphonimide) in a basic medium to the corresponding trifluoromethanesulphonate of formula (XIV):
A-G1-Cy-OSO2CF3xe2x80x83xe2x80x83(XIV) 
wherein A, G1 and Cy are as defined hereinbefore,
which is subjected, under conditions of catalysis by a suitable palladium compound, to the action of a boric acid compound (RbB(OH)2) or of a tin compound (RbSnBu3) (wherein Rb represents a grouping of formula (XV):
B-G3-Cy-W3xe2x80x94(CH2)mxe2x80x94W2xe2x80x94(CH2)nxe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(XV) 
wherein B, G3, Cy, W3, m, W2 and n are as defined hereinbefore, with the proviso that it is not possible to have two consecutive hetero atoms in the xe2x80x94W3xe2x80x94(CH2)mxe2x80x94W2xe2x80x94 chain and that the chain so defined may have one or more unsaturated bonds),
to yield a compound of formula (I/b), a particular case of the compounds of formula (I):
A-G1-Cy-CH2xe2x80x94(CH2)nxe2x80x94W2xe2x80x94(CH2)mxe2x80x94W3-Cy-G3-Bxe2x80x83xe2x80x83(I/b) 
wherein A, G1, Cy, n, W2, m, W3, Cy, G3 and B are as defined hereinbefore (with the proviso that it is not possible to have two consecutive hetero atoms in the xe2x80x94W2xe2x80x94(CH2)mxe2x80x94W3xe2x80x94 chain and that the chain so defined may have one or more unsaturated bonds),
which compounds of formula (I/c), a particular case of the compounds of formula (I):
A-G1-Cy-W1xe2x80x94(CH2)nxe2x80x94W2xe2x80x94(CH2)mxe2x80x94CH2-G3-Bxe2x80x83xe2x80x83(I/c) 
wherein A, G1, Cy, W1, n, W2, m, G3 and B are as defined hereinbefore (with the proviso that it is not possible to have two consecutive hetero atoms in the xe2x80x94W1xe2x80x94(CH2)nxe2x80x94W2xe2x80x94 chain and that the chain so defined may have one or more unsaturated bonds),
are obtained according to a similar procedure starting from a compound of formula (XIVxe2x80x2):
B-G3-Cy-OSO2CF3xe2x80x83xe2x80x83(XIVxe2x80x2) 
wherein B, G3 and Cy are as defined hereinbefore,
or is treated, under coupling conditions using, for example, nickel or palladium compounds, with a compound of formula (XIVxe2x80x2) to yield a compound of formula (I/d), a particular case of the compounds of formula (I):
A-G1-Cy-Cy-G3-Bxe2x80x83xe2x80x83(I/d) 
wherein A, G1, Cy, G3 and B are as defined hereinbefore,
the totality of the compounds (I/a) to (I/d) constituting the compounds of formula (I) which may be purified, if desired, by a conventional purification technique, are separated, where appropriate, into their isomers according to a conventional separation technique, and converted, if necessary, into addition salts thereof with a pharmaceutically acceptable acid or base.
The compounds of formula (V) are readily accessible to the person skilled in the art according to methods described in the literature.
The compounds of the invention and the pharmaceutical compositions containing them have proved to be useful in the treatment of disorders of the melatoninergic system.
The invention relates also to compounds of formula (XIIxe2x80x3):
A-G1-Cy-W4xe2x80x94(CH2)nxe2x80x94W2xe2x80x94(CH2)m-Exe2x80x2xe2x80x83xe2x80x83(XIIxe2x80x3) 
wherein A, G1, Cy, W4, n, W2 and m are as defined hereinbefore and Exe2x80x2 represents a hydroxyl group or a halogen atom (fluorine, chlorine, bromine or iodine),
with the proviso that
when Cy represents a naphthalene, and when simultaneously G1-A represents a grouping xe2x80x94(CH2)2xe2x80x94NR1C(Q)R2 or xe2x80x94(CH2)2xe2x80x94NR1C(Q)NR2R3 (wherein R1, R2 and R3 are as defined hereinbefore), then the xe2x80x94W4xe2x80x94(CH2)nxe2x80x94W2xe2x80x94(CH2)mxe2x80x94 chain cannot represent an xe2x80x94O-alkyl-chain,
the compound of formula (XIIxe2x80x3) cannot represent N-{2-[5-(2-hydroxyethoxy)-1H-indol-3-yl]ethyl}acetamide,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base,
as synthesis intermediates but also as compounds for use in the treatment of disorders associated with the melatoninergic system.
Pharmacological study of the compounds of the invention has in fact shown that they are atoxic, have a very high affinity for melatonin receptors and have substantial activities in respect of the central nervous system, and, in particular, therapeutic properties in respect of sleep disorders, anxiolytic, antipsychotic and analgesic properties, as well as properties in respect of microcirculation have been found, enabling it to be established that the compounds of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal affective disorder, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jetlag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson""s disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory loss, Alzheimer""s disease, and in cerebral circulation disorders. In another field of activity, it appears that the compounds of the invention can be used in the treatment of sexual dysfunctions, that they have ovulation-inhibiting and immunomodulating properties and are capable of being used in the treatment of cancers.
The compounds will preferably be used in the treatment of seasonal affective disorder, sleep disorders, cardiovascular pathologies, insomnia and fatigue due to jetlag, appetite disorders and obesity.
For example, the compounds will be used in the treatment of seasonal affective disorder and sleep disorders.
The present invention relates also to pharmaceutical compositions comprising at least one compound of formula (I) on its own or in combination with one or more pharmaceutically acceptable excipients.
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration and especially tablets or dragxc3xa9es, sublingual tablets, sachets, paquets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.
The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication or any associated treatments, and ranges from 0.01 mg to 1 g per 24 hours in one or more administrations.
The following Examples illustrate the invention but do not limit it in any way. The following Preparations yield compounds of the invention or synthesis intermediates for use in the preparation of the invention.
Preparation 1: N-[2-(7-Hydroxy-1-naphthyl)ethyl]-acetamide
Under an inert atmosphere, 27.5 mmol of the boron tribromide/dimethyl sulphide complex are dissolved in 100 ml of dichloromethane and stirred for 15 minutes at room temperature. A solution of 13.7 mmol of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide in 50 ml of dichloromethane is added, and the reaction mixture is refluxed for 30 hours. After cooling, the reaction mixture is hydrolysed cautiously and the dichloromethane is removed by evaporation. The mixture is then extracted with ethyl acetate, and the combined organic phases are washed with an aqueous 1M potassium hydrogen carbonate solution. The organic phase is dried over magnesium sulphate and concentrated to yield the title compound. White solid.
Melting point: 125-126xc2x0 C.
Preparations 2 to 19 are obtained by proceeding as for Preparation 1 starting from the appropriate substrate:
Preparation 2: N-Butyl-Nxe2x80x2-[2-(7-hydroxy-1-naphthyl)ethyl]urea
Preparation 3: N-[2-(7-Hydroxy-1-naphthyl)ethyl]cyclopropanecarboxamide
Preparation 4: 4-(7-Hydroxy-1-naphthyl)-N-methylbutanamide
Preparation 5: N-[2-(7-Hydroxy-1-naphthyl)ethyl]-3-butenamide
Preparation 6: N-[2-(7-Hydroxy-3-phenyl-1-naphthyl)ethyl]acetamide
Preparation 7: N-[2-(5-Hydroxy-1-benzothiophen-3-yl)ethyl]butanamide
Preparation 8: 2,2,2-Trifluoro-N-[2-(5-hydroxy-1-benzothiophen-3-yl)ethyl]-acetamide
Preparation 9: 4-(5-Hydroxy-1-benzofuran-3-yl)-N-methylbutanamide
Preparation 10: N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamide
Preparation 11: N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]-Nxe2x80x2-propylurea
Preparation 12: N-{2-[5-Hydroxy-2-(3-methoxybenzyl)-1-benzofuran-3-yl]ethyl}acetamide
Preparation 13: N-[2-(5-Hydroxy-1H-indol-3-yl)ethyl]-Nxe2x80x2-propylthiourea
Preparation 14: N-[2-(5-Hydroxy-1H-indol-3-yl)ethyl]cyclobutanecarboxamide
Preparation 15: N-[2-(5-Hydroxy-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-acetamide
Preparation 16: N-[2-(5-Hydroxy-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-Nxe2x80x2-propylurea
Preparation 17: N-[2-(6-Hydroxy-3,4-dihydro-2H-chromen-4-yl)ethyl]acetamide
Preparation 18: N-[(6-Hydroxy-2H-chromen-3-yl)methyl]butanamide
Preparation 19: N-[(7-Hydroxy-1,4-benzodioxin-2-yl)methyl]-Nxe2x80x2-propylurea
Preparation 20: N-[2-(7-Mercapto-1-naphthyl)ethyl]benzamide
Step A: N-[2-(7-Hydroxy-1-naphthyl)ethyl]benzamide
The procedure is as for Preparation 1 starting from N-[2-(7-methoxy-1-naphthyl)ethyl]benzamide.
Step B:. N-[2-(7-Mercapto-1-naphthyl)ethyl]benzamide
The product obtained in Step A (9 mmol) is added, with stirring, to a solution of potassium hydroxide (10 mmol) dissolved in 15 ml of water and 16 ml of tetrahydrofuran. The solution is cooled using a bath of ice and salt, and dimethylthiocarbamoyl chloride (9 mmol) dissolved in tetrahydrofuran (15 ml) is added dropwise with stirring. After stirring for half an hour while maintaining the cold temperature, the reaction mixture is extracted with chloroform. The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated under reduced pressure. The residue is taken up in diphenyl ether (10 ml) and refluxed for one hour under a nitrogen atmosphere. The diphenyl ether is removed by evaporation under reduced pressure until a solution of about 2 ml has been obtained. The 2 ml of distillate, which are still hot, are poured carefully into 50 ml of hexane to yield, after cooling, a solid which is isolated by filtration. The solid collected in that manner is added to a solution of potassium hydroxide (380 mg) dissolved in a water/methanol mixture (1 ml/10 ml). The solution is refluxed for 12 hours and then cooled and concentrated under reduced pressure. The residue is taken up in 20 ml of chloroform and extracted 3 times with water. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is chromatographed over silica gel to yield the title product.
Preparation 21: 2-Phenyl-N-[2-(5-mercapto-1-benzofuran-3-yl)ethyl]acetamide
The procedure is as for Preparation 20 starting from 2-phenyl-N-[2-(5-hydroxy-1-benzofuran-3-yl)ethyl]acetamide.
Preparation 22: N-[2-(5-Amino-1-benzothiophen-3-yl)ethyl]cyclohexanecarboxamide
Step A: N-[2-(5-Hydroxy-1-benzothiophen-3-yl)ethyl]cyclohexanecarboxamide
The procedure is as for Preparation 1 starting from N-[2-(5-methoxy-1-benzothiophen-3-yl)ethyl]cyclohexanecarboxamide.
Step B: N-[2-(5-Bromo-1-benzothiophen-3-yl)ethyl]cyclohexanecarboxamide
Triphenylphosphine (10 mmol) and acetonitrile (70 ml) are poured into a 150 ml three-necked flask equipped with a dropping funnel, a cooler on top of which is mounted a tube filled with calcium chloride, and a mechanical stirrer. The solution is cooled using an ice-bath while maintaining stirring, and bromine (10 mmol) is added. When the addition is complete, the ice-bath is withdrawn and then the product obtained in Step A (8 mmol) is added. The reaction mixture is stirred at 60-70xc2x0 C. until the starting material has disappeared. At the end of the reaction, the mixture is filtered, and then the filtrate is concentrated under reduced pressure. The residue is taken up in ethyl acetate, washed with water and then with a saturated potassium hydrogen carbonate solution, and once again with water, and then dried over magnesium sulphate and concentrated under reduced pressure. The residue is filtered over silica gel to yield the title product.
Step C: N-[2-(5-Iodo-1-benzothiophen-3-yl)ethyl]cyclohexanecarboxamide
A mixture of the product obtained in Step B (2 mmol), potassium iodide (30 mmol) and copper(I) iodide (10 mmol) in hexamethylphosphoramide (6 ml) is heated at 150-160xc2x0 C. with stirring under a nitrogen atmosphere until a 90% conversion rate has been reached. Dilute hydrochloric acid is then added, followed by ether, and the mixture is then filtered to remove the insoluble copper(I) salts. The organic phase is separated off, washed with a solution of sodium sulphite and with water, dried over magnesium sulphate and evaporated to yield a residue which is chromatographed over silica gel to yield the title product.
Step D: N-[2-(5-Vinyl-1-benzothiophen-3-yl)ethyl]cyclohexanecarboxamide
15 mmol of the product obtained in Step C, 16 mmol of vinyl tributyltin and 0.43 mmol of tetrakis(triphenylphosphine)palladium, are heated at 110xc2x0 C., with stirring, for 3 hours in 30 ml of N-methylpyrrolidinone. After removal of the solvent by evaporation, the residue is taken up in 20 ml of dichloromethane and treated with an aqueous 10% potassium fluoride solution. Extraction, concentration under reduced pressure and chromatography over silica gel yield the pure title product.
Step E: N-[2-(5-Formyl-1-benzothiophen-3-yl)ethyl]cyclohexanecarboxamide
1.10 g of osmium tetroxide in 2-methyl-2-propanol and then 8.70 g of sodium periodate are added at room temperature to a solution of 10 mmol of the product obtained in Step D in a mixture of 50 ml of dioxane and 25 ml of water. After stirring overnight at room temperature, the suspension is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is taken up in dichloromethane. The organic phase is washed with water, dried and evaporated. The residue is purified by chromatography over silica gel to yield the title product.
Step F: 3-{2-[(Cyclohexylcarbonyl)amino]ethyl}-1-benzothiophene-5-carboxylic Acid
2.7 g of potassium permanganate in 50 ml of an acetone/water mixture (50/50) are added at room temperature to a solution of 6.88 mmol of the product obtained in Step E in 30 ml of acetone. The solution is stirred for 2 hours at room temperature and then filtered. The filtrate is concentrated under reduced pressure and chromatographed over silica gel to yield the title product.
Step G: 3-{2-[(Cyclohexylcarbonyl)amino]ethyl}-1-benzothiophene-5-carboxylic Acid Chloride
5 mmol of the product obtained in Step F are dissolved in 40 ml of thionyl chloride. After stirring under an inert atmosphere for 1 hour, the thionyl chloride is removed by evaporation under reduced pressure to yield the title product.
Step H: N-[2-(5-Amino-1-benzothiophen-3-yl)ethyl]cyclohexanecarboxamide
A solution of the product obtained in Step G (20 mmol) in dichloromethane (30 ml) containing tetrabutylammonium bromide (20 mg) is cooled in an ice-bath. After the addition of sodium azide (25 mmol) dissolved in 5 ml of water, the solution is stirred vigorously at 0xc2x0 C. for 2 hours. The organic phase is separated off, washed with water (2xc3x975 ml) and dried over magnesium sulphate. After filtration, trifluoroacetic acid (30 mmol) is added and the solution is stirred under reflux for 60 hours. After cooling, the organic phase is washed with a saturated sodium hydrogen carbonate solution (2xc3x975 ml) and concentrated under reduced pressure. The residue is then taken up in methanol (20 ml), and water (80 ml) and then potassium carbonate (30 mmol) are added. After stirring at room temperature for 20 hours, the reaction mixture is concentrated under reduced pressure to a volume of about 60 ml, and is then extracted 3 times with ether (3xc3x9750 ml). After drying over sodium sulphate, the organic phase is filtered and then evaporated under reduced pressure. The residue is chromatographed over silica gel to yield the title product.
Preparation 23: 2-(5-Amino-1-benzofuran-3-yl)-N-hexylacetamide
The procedure is as for Preparation 22.
Preparation 24: 8-[2-(Acetylamino)ethyl]-2-naphthyl Trifluoromethanesulphonate
60 ml of triethylamine are added to a solution of 0.07 mol of the compound obtained in Preparation 1 in one liter of dichloromethane. The reaction mixture is refluxed until dissolution, and then 0.1 mol of phenyl bis(trifluoromethanesulphonimide) and 0.75 mol of potassium carbonate are added. After 4 hours"" reflux, the mixture is washed with one liter of 1M sodium hydrogen carbonate and then with one litter of 1M hydrochloric acid. The organic phase is dried, concentrated and purified by chromatography over silica gel to yield the title product.
Preparation 25: 3-{2-[(Cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-yl Trifluoromethanesulphonate
The procedure is as for Preparation 24 starting from the product obtained in Preparation 10.
Preparation 26: 3-[2-(Acetylamino)ethyl]-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl Trifluoromethanesulphonate
The procedure is as for Preparation 24 starting from the compound obtained in Preparation 15.
Preparation 27: N-[2-(7-Hydroxy-1,2,3,4-tetrahydro-1-naphthalenyl)ethyl]-acetamide
The procedure is as for Preparation 1 starting from N-[2-(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)ethyl]acetamide.
Melting point: 149-150xc2x0 C.
Preparation 28: N-{2-[5-Hydroxy-1-(phenylsulphonyl)-1H-indol-3-yl]ethyl}acetamide
Step A: N-{2-[5-Methoxy-1-(phenylsulphonyl)-1H-indol-3-yl]ethyl}acetamide
Dissolve 5 g (21.5 mmol) of melatonin in 150 ml of dichloromethane. With stirring, add 3.41 g (84 mmol) of sodium hydroxide and 0.35 g (0.9 mmol) of tetrabutylammonium hydrogen sulphate. Cool the mixture in an ice-bath, and add 4.06 ml (31.5 mmol) of benzenesulphonyl chloride dropwise. After stirring overnight at room temperature, filter off the excess sodium hydroxide and the catalyst. Remove the solvent by evaporation in vacuo, and recrystallise the resulting solid.
Melting point: 140-141xc2x0 C.
Step B: N-{2-[5-Hydroxy-1-(phenylsulphonyl)-1H-indol-3-yl]ethyl}acetamide
The procedure is as for Preparation 1 starting from the compound obtained in Step A.
Melting point: 205-206xc2x0 C.
Preparation 29: N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]acetamide
The procedure is as for Preparation 1 starting from N-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]acetamide.
Melting point: 140xc2x0 C.
Preparation 30: N-[2-(5-Hydroxy-1H-indol-3-yl)ethyl]acetamide
The procedure is as for Preparation 1 starting from melatonin.
Colourless oil.
Preparation 31: Tert-butyl 2-(7-hydroxy-1-naphthyl)ethyl Carbamate
In a 100 ml round-bottomed flask, suspend 8-(2-aminoethyl)-2-naphthol hydrobromide (3 g, 1.12 mmol) in 30 ml of dichloromethane and add triethylamine (3.88 ml, 2.8 mmol). Cool the reaction mixture to 0xc2x0 C. using an ice-bath, and add di-tert-butyl dicarbonate (2.2 g, 1 mmol) dissolved in 10 ml of dichloromethane dropwise. Stir the reaction mixture at room temperature for 4 hours. Wash the reaction mixture with an aqueous 0.5M hydrochloric acid solution and then with water. Dry the organic phase over magnesium sulphate and evaporate it under reduced pressure. Recrystallise the resulting residue from cyclohexane/toluene (1/1).
Melting point: 72-73xc2x0 C.
Preparation 32: N-[2-(5-Hydroxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]-acetamide
The procedure is as for Preparation 1 starting from N-[2-(5-methoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]acetamide.
Preparation 33: 3-[2-(Acetylamino)ethyl]-1H-indol-5-yl Trifluoromethanesulphonate
The procedure is as for Preparation 24 starting from the compound obtained in Preparation 30.
Preparation 34: N-[2-(5-Hydroxy-1-benzothiophen-3-yl)ethyl]acetamide
The procedure is as for Preparation 1 starting from N-[2-(5-methoxy-1-benzothiophen-3-yl)ethyl]acetamide.
Melting point: 166-168xc2x0 C.
Preparation 35: N-[2-(7-Hydroxy-2-methoxy-1-naphthyl)ethyl]acetamide
The procedure is as for Preparation 1 starting from N-[2-(2,7-dimethoxy-1-naphthyl)ethyl]acetamide.